PREPARATION OF 1-ACETOXY-3-(ALKYL)-6,6,9-TRIMETHYL-7,8,9,10-TETRAHYDRO-6H-DIBENZO{8 b,d{9 {0 PYRAN ISOMERS

ABSTRACT

A novel process and novel intermediates in the synthesis of the novel optically-active isomers of 1-acetoxy-3(alkyl)-9-methyl7,8,9,10-tetrahydro-6H-dibenzo (b,d)pyran as incapacitating agents. Those intermediates are prepared by reducing a mixture comprising a ketone, an alcohol and borohydride to the carbinol, treating said carbinol with a trihalide and converting the trihalide product to a malonic ester, hydrolyzing said ester and separating the aqueous phase, acidifying said aqueous phase results in the preparation of an isomeric mixture of alkyldialkoxyhydrocinnamic acid.

United States Patent Aaron et al.

PREPARATION OF l-ACETOXY-3- (ALKYL)-6,6,9-TRIMETHYL-7,8,9,l0- ag'rg nrnno-an-nmmzoma PYRAN 'ISOMERS Inventors: Herbert S. Aaron, Baltimore; Clyde Parker Ferguson, Jr., Bel Air, both of Md.

The United States of America as represented by the Secretary of the Army Filed: July 10,1968

Appl. No.: 743,907

Assignee:

References Cited UNITED STATES PATENTS 5/1950 Adams ..260/345.3

[451 Sept. 26, 1972 Primary Examiner-Leland A. Sebastian Attorney+-l-larry M. Saragovitz, Edward J. Kelly, Herbert Berl and Jacob Ziegler [57] ABSTRACT A novel process and novel intermediates in the synthesis of the novel optically-active isomers of l-acetoxy- 3( alkyl)-9-methyl-7,8,9, l0-tetrahydro-6H-dibenzo [b,d]pyran as incapacitating agents. Those intermediates are prepared by reducing a mixture comprising a ketone, an alcohol and borohydride to the carbinol, treating said carbinol with a trihalide and converting the trihalide product to a malonic ester, hydrolyzing said ester and separating the aqueous phase, acidifying said aqueous phase results in the preparation of an isomeric mixture of alkyl-dialkoxyhydrocinnamic acid.

6 Claims, N0 Drawings PREPARATION OF l-ACETOXY-3-(ALKYL)-6,6,9- TRlMETHYL-7,8 ,9, lO-TETRAHYDRO-6H- DIBENZOH PYRAN ISOMERS DEDICATORY CLAUSE The invention described herein may be manufactured, used, and licensed by or for the Government for governmental purposes without the payment to us of any royalty thereon.

This invention relates to the preparation of various stereoisomers of tetrahydrocannabinol congeners.

The object of this invention is the process for preparing the various optical isomers of l-hydroxy-3-(l,2- dimethylheptyl )-6,6,9-trimethyl-7,8 ,9, l -tetrahydro-6 H-dibenzo[b,d]pyran and its corresponding acetate derivative. I

It is a further objective to prepare a new intermediate compound in order to prepare the final isomers.

The synthesis of the racemic mixture of the tetrahydrocannabinol congener l-hydroxy-3-(l,2- dimethylheptyl)-6,6,9-trimethyl-7 ,8 ,9, l0-tetrahydro 6 H-dibenzo[b,d]pyran is described by Adams et al., J. Am. Chem. Soc., 67, 1534 (1945); Adams et al., ibid, 70, 664 1948). The procedure is summarized in part:

CH CH3 CH3 CH By this path, carbinol 1 obtained in two steps from 3,5- dimethoxybenzamide was dehydrated to the olefin 2, and then reduced to the alkane compound 3 which was demethylated to compound 4 and condensed with 2- carbethoxy-S-methylcyclohexanone to prepare pyrone 6 then to pyran 7.

Reinvestigation of the Adams et al reaction sequence revealed that the dehydration tends to give, initially, the vinyl olefin:

=CH1 3080; 6 03, 898 cm.

Erythro CHsO Three CHaO COOH COOH CHiO CHsO The erythro and threo configurations of the stereoisomers of final compound, l-acetoxy-3(l', 2- dimethylheptyl )-6,6,9-trimethyl-7,8 ,9, l 0-tetrahydro-6 l-l-dibenzo[b,d]pyran are:

Erythro The method according to our invention is utilizing 3,S-dimethoxyacetophenone (10) as the starting material which was reduced with sodium borohydride to the corresponding carbinol (l l), which was then treated with phosphorus tribromide to form the corresponding bromo analog [oz-(3,5-dimethoxyphenyl)ethylbromide], which was not isolated, but was reacted with a C to C dialkyl malonate in a malonic ester synthesis. The resulting product, which was not isolated, was hydrolyzed with alkali metal hydroxide then acidified and decarboxylated by refluxing in xylene or diethylene glycol dimethyl ether to form compound 1 2, a-amyl-B-methyl-3,S-dimethoxyhydrocinnarnic acid. The latter compound is an isomeric mixture that was separated into an erythro isomer salt with dicyclohexylamine, and a threo isomer salt with benzylamine. Separately the erythro and threo isomers were regenerated from their salts and then each separate isomer was treated with the d and 1 forms of a-methylbenzylamine producing four separate isomers, that is, d and l erythro form and d and l threo form. Each of the latter four optical isomers was reduced with lithium aluminum hydride to give its corresponding alcohol optical isomers, that is 2-(amyl)-3- (3,S-dimethoxyphenyl)butanol compound (13). Each isomer of compound 13 was converted to the ptoluenesulfonate ester, e.g., 2-(amyl)-3-(3,5-dimethoxyphenyl)butyl-p-toluenesulfonate, which was not isolated but reduced with lithium aluminum hydride to the four isomers of compound 3, 2-(3,5-dimethoxyphenyl)- 3-methyloctane. Each of the latter four optical isomers was demethylated (compound 4), then separately treated with the d and I forms of 2-carbethoxy-5- methylcyclohexanone (compound 5), producing the corresponding eight isomers l-hydroxy-3-(l,2- dimethylheptyl )-9-methyl-7 ,8,9 l 0-tetrahydro-6H- dibenzo[b,d]pyrone, compound 6. The latter each isomer was converted into the corresponding pyran compound 7, then to the corresponding acetate ester 1- acetoxy-3-( 1 ,Z-dimethylheptyl)-6,6,9-trimethyl- 7,8,9,lO-tetrahydro-6H-dibenzo[b,d]pyran-(acetate of The alcohols which may be employed are lower alkyl alcohols containing from one to four carbon atoms and polyhydric alcohols as ethylene glycol or 1,2,3- propanetriol.

The extracting medium may be diethyl ether, benzene, toluene or trichloromethane.

The pharmacological evaluation of the compounds described in this disclosure was determined by Visual Discrimination Test (VDT), lethal or minimum dose for potency was administering intravenously various proportions (milligrams/kilogram) of the compound into various test animals eg, mice or monkey, using the method of the The Search For and Selection of Toxic Chemical Agents for Weapons Systems" disclosed in the Edgewood Arsenal, Maryland Publication (CRDL SOP -3, 6 May 1965).

Visual Discrimination Test procedure is a conditioned avoidance-escape task combined with a choice discrimination task employing a primate, monkey, as a test animal.

LD is the lowest dose in milligrams in compound per kilogram of animal required to be lethal in 50% of the tested animals. MED is the lowest dose in milligrams of compound per kilogram of animal required to give any visible physiological effects (e.g., locomotor) in 50% of the tested animals. The quotient of the ratio LD /MED is the margin of safety that is the higher the numerical quotient the greater the proportion of agent can be used before causing death and therefore a better incapacitating agent.

aforementioned Maryland Publication.

TABLE I Visual Discrimination Test-Monkey Compound Proportion (0.1 mg/kg B Negative isomer 1 Positive isomer 2 Positive isomer 3 Negative isomer 4 Positive isomer 5 Negative isomer 6 Positive isomer 7 Negative isomer 8 Negative isomer l-8 Negative B: Racemate; l-acetoxy-3-( l ,2-dimethylheptyl)-6,6,9- trimethyl-7 ,8 ,9 l 0-tetrahydro-6H-dibenzo b,d] pyran (acetate of 7), prepared according to Adams. isomers 1 through 8: are the separated optically-active isomers of the racemate prepared according to this invention.

isomer 1-8: is the separated optically-active isomers 1 through 8 are recombined to form a racemate mixture.

TABLE 11 Compound Potency (Mice) L0,, MED LB /MED A l0.0 0.32 3 l B 72.5 0. l 0 725 A: 1 -hydroxy-3-( l ,Z-dimethylheptyl)-6,6,9-trimethyl- 7 ,8 ,9, l 0-tetrahydro-6I-i-dibenzo[b,d]pyran, racemate. B: l-acetoxy-3-( 1,2-dimethylheptyl)-6,6,9-trimethyl- 7,8,9,l0-tetrahydro-6l-i-dibenzo[b,d]pyran (acetate of 7 racemate.

We have found unexpected and unobvious results in the ability of the test animal to carry out the conditional avoidance-escape task which is directly relatable to incapacitation activity (Table i). The racemic mixture demonstrated no activity as compared with the positive responses upon employment of the opticallyactive isomers. in addition, recombining the separated isomers into a synthetic racemate, isomer l-8, there was again no activity as demonstrated by the original racemate. We have clearly shown that the isolated isomers have desirable incapacitating activity not shown by the racemate. As is well recognized, the activity of the racemate is carried forward to the isomers with greater effect. Here, we have shown that the racemate produces no activity and the isomers l, 2, 4, and 6 did exhibit activity as reflected in the positive notation in Table l.

EXAMPLE 1 Preparation of a-(3,S-dimethoxyphenyl)ethanol..

A mixture comprising about 83 g (0.46 mole) of 3,5- dimethoxyacetophenone in 50 ml of methanol added dropwise with stirring to a solution of 18 g of sodium borohydride in 300 ml of methanol containing lg of sodium hydroxide as refluxed for about 30 minutes.

The methanol was removed in a distillation step and about 100 ml of water was added during said step. The reacted mixture was cooled, extracted with several portions of ether, e.g. diethyl ether, being combined, dried, filtered, concentrated and distilled gave about g of a-( 3,5-dimethoxyphenyl)ethanol, compound 1 1.

EXAMPLE 2 A mixture comprising about 28.5 g (0.16 mole) of a- (3,5-dimethoxyphenyl) ethanol in 70 ml of ether in an ice bath was treated with dropwise addition requiring about 1 hour of phosphorus tribromide solution comprising 18 ml phosphorus tribromide and 70 ml ether with subsequent warming to room temperature, then refluxed for about 2 hours on a steam bath, cooled and pouredover crushed ice. The reacted mixture was extracted with 3 portions of ether. The ether extracts were combined and washed with 10% solution of bicar bonate, then water and dried gave a-(3,5-dimethoxyphenyl)ethylbromide solution which was concentrated by ether removal on a steam bath, then under anhydrous conditions with subsequent addition to a solution comprising about 42 g (0.18 mole) diethyl n-amylmalonate and 300 ml of anhydrous ethanol containing about 4.6g (0.20 mole) of freshly dissolved sodium. The mixture was stirred at room temperature for about 100-140 minutes. Mild distillation then removed the ether and completed the reaction. Distillation was continued with water addition when the head temperature was about 76-80 C. and additional water was added until head temperature was about -l03 C. The mixture was then cooled and extracted with three 250 ml portions of ether which were combined and concentrated by distillation to give rise to the crude 0t-(3,5- dimethoxyphenyl) amylmalonate. The latter ester was hydrolyzed with stirring for about 5-7 hours at 150-17 0 C. in ethylene glycol containing about 35 g of sodium hydroxide, then subsequently cooled, diluted to 1,500 ml with water and washed with ether. The aqueous phase was acidified e.g., mineral acid, e.g., H SO, or HCl, and extracted with four 200 ml portions of ether. The extracts were combined, concentrated by distillation on a steam bath and the residue as taken up in 150 ml of xylene, distilled to remove residual ether and water and then refluxed (head temperature of l30150 C.) for about 6 hours. The xylene was removed under reduced pressure of 0.10 0.20 mm at a pot temperature of 115 C. and gave crude a-amyl-B- methyl-3,5-dimethoxyhydrocinnamic acid as an isomeric mixture, compound 12.

EXAMPLE 3 Preparation of Acid isomer I erythro) a. A mixture comprising about 34g of crude a-amyl- B-methyl-3,S-dimethoxyhydroCinnamic acid, Example 2, was dissolved with warming in about -150 ml of ether, then combined with 22-26 g of dicyclohexylamine and placed overnight in the cold, filtered and gave about 19 g of salt and Filtrate I. The salt dicyclohexylamine derivative, m.p. l31-135 C was recrystallized from about 250 ml acetone with m.p. about l38-l40 C.

Anal. Calcd. for C i-i NO.: C, 73.2; H 10.4; 0, 13.5;

equiv. wt. 476 Found: C, 73.6; H, 10.6; 0, 13.5;

equiv. wt. 477

b. The salt, from (a) supra, was dissolved in a solution comprising 30-40 ml of methanol, acidified with 10-15 ml of 6N hydrochloric acid and diluted with 800 to 1,000 ml water formed an oil upon cooling, scratched and gave 10 g of dl-a-amyl-B-methyl-3,5- dimethoxyhydrocinnamic acid, erythro, m.p. 55-57 C., which was recrystallized from petroleum ether.

EXAMPLE 4 ml benzene and gave about 17 g of the derivative, m.p. 121-122 C.

Anal. Calcd. for C H NO C, 71.8; H, 8.8; O, 15.9;

N, 3.5 Found: C, 71.7; H, 8.8; O, 16.0;

b. The benzylamine derivative, from (a) supra, dissolved in a solution comprising 25-35 ml methanol, acidified with 10-15 ml 6N hydrochloric acid and 175-200 ml water formed an oil which solidified in the cold and gave about 11g of dl-a-amyl-B-methyl-3,5- dimethoxyhydrocinnamic acid, Acid lsomer ll (threo), m.p. 54-57 C., recrystallized from petroleum ether, m.p. 5557 C.

Anal. Calcd. for C H ,,O,: C, 69.4; H, 8.9; O, 21.7;

neut. equiv., 294. C, 68.9; H, 8.5; O, 21.4; neut. equiv., 294.

Found:

EXAMPLE a. A mixture comprising about 35g of dlacid isomer 1, (erythro), dl-a-amyl-B-3,S-dimethoxyhydrocinnamic acid, Example 3(b), and an equivalent amount l-amethylbenzylamine in ether (2 to 5 ml per/g of amine) gave l-a-methylbenzylamine d-Acid lsomer 1 (salt), which was recrystallized at least twice from ether ml/g) and gave about 5 g of the above salt, m.p. 96-98 C., [01]?) +22.0(methanol, c 2.0).

b. The amine salt,'from (a) supra, was dissolved in 2N aqueous sodium hydroxide (1O ml/g), washed with ether, followed by petroleum ether, acidified e.g., excess hydrochloric acid, cooled, and gave d-a-amyl-B- methyl-3,S-dimethoxyhydrocinnamic acid, Acid lsomer l, erythro, m.p. 49-52 C., [02],, +3S.6 (methanol, c. 2.2).

EXAMPLE 6 a. The procedure in accordance with Example 5(a) was repeated with the exception of substituting d-ozmethylbenzylamine for the l-a-methylbenzylamine and produced about 9 g of d-a-methylbenzylamine l-acid isomer 1, m.p. 96-98 C., [(1H, 21.8(methanol, c 2.0).

b. The procedure in accordance with Example 5(b) was repeated with the exception of substituting d-amethylbenzylamine l-acid isomer I for the l-a-methylbenzylamine d-acid isomer 1, and gave l-oz-amyl-B- methyl-3,S-dimethoxyhydrocinnamic acid, acid isomer 1, erythro, m.p. 49.5-53 G, [0:1 35.2(methanol, c 2.0).

EXAMPLE 7 a. A mixture comprising -210 g of dl-acid isomer I1, threo, from Example 4(b), d-a-methylbenzylamine and ether (2-5 ml per/g amine) gave the insoluble partially resolved d-a-methylbenzylamine l-acid isomer ll (salt) which was separated from Filtrate 111. The said salt was recrystallized at least five times from ether l5 ml/g) and then recrystallized at least four times from ethyl acetate (5 ml/g) and gave about 11 g substantially of d-oz-methylbenzylamine l-acid isomer ll, [01],, 5.0 (c 4.3).

b. The procedure in accordance with Example 5 (b) was followed with the exception of substituting the d-amethylbenzylamine l-acid isomer I1, Example 7(a), for l-a-methylbenzylamine d-acid isomer 1 and gave [-01- amyl-B-methyl-3,S-dimethoxyhydrocinnamic acid, acid isomer ll, threo, m.p. 78-81 C., [01],, -6.7 (methanol, c 3.7).

EXAMPLE 8 a. The procedure in accordance with Example 7(a) was repeated with the exception of substituting the l-amethylbenzylamine for the d-a-methylbenzylamine and gave about 12 g of partially resolved salt l-a-methylbenzylamine d-a-amyl-B-methyl-3,S-dimethoxyhydrocinnamic acid, [a],, 5.0 (methanol, c 3.5).

b. The procedure in accordance with Example 5(b) was repeated with the exception of substituting l-amethylbenzylamine d-a-amyl-B-methylbenzylamine da-amyl-B-methyl-3,5dimethoxyhydrocinnamic acid (Amine Acid lsomer l) and gave da-amyl-B-methyl- 3,5dimethoxyhydrocinnamic acid, acid isomer l1, threo, m.p. 47-53 C., [011 7. 1 (methanol, 0 3.5).

EXAMPLE 9 a. A mixture comprising about 14.5 g (0.049 mole) of the optically-active isomer d-a-amyl-B-methyl-3,5- dimethoxyhydrocinnamic acid, acid isomer 1, erythro, Example 5(b) or d-a-amylfi-methyl-3,S-dimethoxyhydrocinnamic acid, acid isomer II, threo, Example 8(b), 5-7 g (excess) lithium aluminum hydride and 200-300 ml ether was refluxed for 6-8 hours, cooled and decomposed by successive additions of methanol in ether, then water and finally dilute hydrochloric acid. The aqueous layer was separated, saturated with sodium chloride and extracted with several portions of ether which were combined further extracted with aqueous bicarbonate, the latter acidified without any precipitation indicating complete reaction. The latter treated ether extract was dried, concentrated and distilled (b.p. 134-138 CJI/I Produced the optically-active isomers, compound 13, d-2-(amyl)-3-(3 ,5- dimethoxyphenyhbutanol, alcohol isomer 1, erythro [01],, 35.2 (methanol, 0 2.5), nil 1.5126 or d-2- (amyl)-3-(3,5-dimethoxyphenyl)butanol, alcohol isomer I1, threo, a,,+2.4 (neat, 1 dm), nil 1.5130.

methyl-3,S-dimethoxyhydrocinnamic acid, acid isomer II, threo, Example 7(b), for the corresponding acid isomer I and gave l-2-(amyl)-3-(3,5-dimethoxyphenyl)butanol, alcohol isomer II, threo, 11% 1.5128.

EXAMPLE A refrigerator freezer, for -17 hours, with subsequent pouring over ice, then extracted with several portions of ether which were combined, washed with cold dilute hydrochloric acid (or H 80 until wash water was acidic (pH l3). 1

b. The reduction mixture comprising the combined ether extracts, from (a) above, washed with aqueous bicarbonate, dried, and added in a dropwise manner to a stirring mixture comprising 3-5 g of lithium aluminum hydride and 75 ml ether, was refluxed for 4-5 hours, cooled and decomposed by successive additions of methyl alcohol in ether, then water, and finally dilute hydrochloric acid. The aqueous layer was separated, saturated with sodium chloride and extracted with several portions of ether which were combined, washed with aqueous bicarbonate, then dried and concentrated. The undistilled portion contained the reduced product was eluted with 600 ml of petroleum ether on an activated alumina (l X 4 in.) column.

c. The petroleum ether eluted from (b) above was concentrated, distilled, and gave the d-2-(3,5- dimethoxyphenyl)-3-methyloctane, threo, [011 +36.9 (methanol, c 3.4), n? 1.4980.

EXAMPLE 10B The procedure according to Example 10A was repeated with the exception of substituting l-2-(amyl)-3- (3,5-dimethoxyphenyl)butanol, erythro, Example 9B, for the corresponding alcohol isomer I, erythro, and gave l-2-(3,S-dimethoxyphenyl)-3-methyloctane, threo, [a] 36.2 (methanol, (2 3.3), n, l .4974.

EXAMPLE 10 C The procedure according to Example 10A was repeated with the exception of substituting l-2-(amyl)-3- (3,S-dimethoxyphenyl)butanol, acid isomer II, threo, Example 9(c), for the corresponding alcohol isomer 1, erythro, and gave l-2-(3,S-dimethoxyphenyl)-3- methyloctane, erythro, a -3.2 (neat, 1 dm) nil 0,, EXAMPLE 10D The procedure according to Example 10A was repeated with the exception of substituting d-2-( amyl)-3- (3,5-dimethoxyphenyl)butanol, alcohol isomer ll, threo, Example 9(d), for the corresponding alcohol isomer I, erythro, and gave d-2-( 3,5-dimethoxyphenyl)- 3-methyloctane, erythro, a +3.0 (neat, 1 dm), ni? 1.4967.

EXAMPLE 11 a. A mixture comprising d-2-( 3 ,S-dimethoxyphenyl 3-methyloctane, threo, Example 10A, with about 48 hydrobromic acid in glacial acetic acid under reflux for about 4-6 hours gave rise to a viscous yellow oil, d-2- (3,5-dihydroxyphenyl)-3-methyloctane, threo.

b. The procedure according to (a) supra, was repeated with the exception of substituting l-2-(3,5- dimethoxyphenyl)-3-methyloctane, threo, Example 108, for the corresponding dextrorotatory octane and gave a yellow viscous oil l-2-(3,5-dihydroxypheny)-3- methyloctane, threo.-

c. The procedure according to (a) supra, was repeated with the exception of substituting l-2-(3,5- dimethoxyphenyl)-3-methyloctane, erythro, Example 10C, for the corresponding dextrorotatory octane, threo, and gave l-2-(3,5-dihydroxyphenyl)-3-methyloctane, erythro.

d. The procedure according to (a) supra, was followed with the exception of substituting d-2-(3,5- dimethoxyphenyl)-3-methyloctane, erythro, Example 10D, for the corresponding dextrorotatory octane,

threo, and gave d-2-(3,5-dihydroxyphenyl)-3- methyloxtane, erythro.

EXAMPLE 12A a. A mixture comprising 2.5to 3.0g of d-2-(3,5- dihydroxyphenyl)-3-methyloctane, threo, Example 1 1(a), in 20 ml of dry benzene was treated with 3.0 to 3.5 g of d-2-carbethoxy-5-methylcyclohexanone in 20 ml of dry enzene and 1.6 to 1.8 g of phosphorus oxychloride. The mixture was refluxed for 45 hours, then diluted with ml of benzene. The benzene solution was washed with 10% sodium bicarbonate, dried and concentrated, then chromatographed on activated alumina (l X 4 in.) benzene. The column was eluted with 50 ml portions of 5, l0 and 50% acetone in benzene, then acetone and finally methanol. The first two eluant fractions were evaporated and the residues were triturated with petroleum ether to give tan solids. They were combined and recrystallized utilizing the charcoal treatment from cyclohexane and gave an offwhite to tan powder of d-l-hydroxy-3-(1,2-dimethylheptyl)-9-methyl-7,8,9, lO-tetrahydro-6I-I-dibenzo[ b,d] pyrone, threo, isomer 3, mp. l33135 C., [01],, (methanol, c 1.8).

b. The procedure according to (a) supra was repeated with the exception of substituting l-2-carbethoxy-S-methylcyclohexanone for the corresponding dextrorotatory hexanone and gave l-l-hydroxy-3- (1,2- dimethylheptyI)-9-methyl7,8 ,9, l0-tetrahydro-6I-I- dibenzo[b,d] pyrone, threo, isomer 4, mp. l4ll43 G, [0:1 67 (methanol, c 2.0).

EXAMPLE 123 a. The procedure according to 12(a) was repeated with exception of substituting l-2-(3,5-dihydroxyphenyl)-3-methyloctane, threo, Example ll (b) for the corresponding dextrorotatory octane and gave dl -hydroxy-3-( l,Z-dimethylheptyl)-9-methyl-7,8,9, l tetrahydro-6H-dibenzo [b,d]pyrone, threo, isomer 1, mp. l42-l43, [a] +7l (methanol, 0 1.9).

b. The procedure according to 12(a) was repeated with the exception of substituting l-2-(3,5-dihydroxyphenyl)-3-methyloctane, threo, and I-Z-carbethoxy-S- methylcyclohexanone for the corresponding dextrorotatory octane and dextrotatory hexanone respectively and gave l-l-hydroxy-3(1,2-dirnethylheptyl )-9-methyl-7 ,8 ,9 l O-tetrahydro- 6H-dibenzo b,d ]pyrone, threo, isomer 2, mp. 13 l133 C., [ab-146 (methanol, c 1.9).

EXAMPLE 13A a. The procedure according to Example 12A(a) was repeated with the exception of substituting d-2-(3,5- dihydroxyphenyl)-3-methylocta.ne, erythro, Example ll(d) for the corresponding d-2-(3,5-dihydroxyphenyl)-3-methyloctane, threo, and gave d-hydroxy-3-(l ,2- dimethylheptyl)-9-methyl-7,8,9,l0-tetrahydro-6H- dibenzo[b,d]pyrone, erythro, isomer 7, mp. 135.5 l 37.5C., [0410+ 118 (methanol, c 0.7). The procedure according to (a) supra was repeated with the exception of substituting I-Z-carbethoxy-S-methylcyclohexanone for the corresponding dextrorotatory hexanone and gave l-1-hydroxy-3-(1,2-dimethylheptyl)-9-methyl-7,8,9,l0-tetrahydro-6H-dibenzo[b,d] pyrone, erythro, isomer 8, mp. 135l38 C., [41],, 95 (methanol, c 0.7).

EXAMPLE 138 a. The procedure according to Example 12A(a) was repeated with the exception of substituting l-2-(3,5- dihydroxyphenyl)-3-methyloctane, erythro, Example 1 1(0), for the dextrorotatary octane, threo, and i-2-carbethoxy-S-methylcyclohexanone for the corresponding dextrorotatory hexanone, and gave 1-l-hydroxy-3- 1 ,Z-dimethylheptyl)-9-methyl-7,8,9, IO-tetrahydro- 6H-dibenzo[b,d]pyrone, erythro, isomer 6, mp. 135137 C., [01],, +l08 (methanol, c 0.6).

b. The procedure according to Example 12A(b) was repeated with the exception of substituting I-2-(3,5- dihydroxyphenyl)-3-methyloctane, erythro, Example ll(c), for the dextrorotatory octane, threo, and I-2- carbethoxy-S-methylcyclohexanone for the corresponding dextrorotatory hexanone, and gave [-1- hydroxy-3-( l,Z-dimethylheptyl)-9-methyl-7,8,9, l 0- tetrahydro-6H-dibenzo[b,d]pyrone, erythro, isomer 6, m.p. 135l37 C., [ad -108 (methanol, 00.6).

EXAMPLE 14 a. A mixture comprising 5.0g methyl iodide in 10 ml of dry ether was added to 0.7 g magnesium and 10 ml dry ether, then refluxed for 20-40 minutes. The dpyrone, threo, isomer 3, Example 12A(a) in 20 ml of dry benzene was added dropwise, then refluxed for 20-40 minutes. The ether was distilled off and refluxing was continued for 14-18 hours. The mixture was then cooled, ice bath, and a solution of 3.0 g of ammonium chloride in 15 ml water was added dropwise. The mixture was then warmed to room temperature, carefully acidified with a solution of 3 ml of sulfuric acid in 10 ml of water, and stirred for 35-55 minutes. The layers were separated and the aqueous layer was extracted with several portions of benzene, combined, dried and concentrated to a red viscous oil as the pyran which was subsequently converted to the corresponding acetate ester by the following method.

A mixture comprising pyran, 10 ml of acetic anhydride, and 0.35 sodium acetate was refluxed with stirring for 3 hours, cooled, poured over ice and an oil separated. The oil was extracted with petroleum ether, washed with l0sodium bicarbonate solution until no longer acidic. The organic phase was dried, concentrated and then chromatographed on a column (1 X 3.5 in.) of silicic acid in petroleum ether, then eluated with petroleum ether containing 2% ether. The fluorescent 100 ml forerun was discarded, and the product eluted in the second 100 ml fraction. The solvent removed under reduced pressure and produced substantially colorless, clear viscous oil of d-l-acetoxy-3-( 1,2- dimethylheptyl)-6,6,9-trimethyl-7,8 ,9, 10-tetrahydro-6 H-dibenzo [b,d]pyran, threo, isomer 3, [a] +133 (methanol, c 0.8).

b. The procedure in accordance with (a) supra was repeated with the exception of substituting the members of the group consisting of l-pryone, threo, isomer 4, Example 12A(b), D-pyrone (threo, isomer 1, Example 12B(a));l-pyrone (threo, isomer b 2, Example 12B(b)), d-pyrone (erythro, isomer 7, Example 13A(a)): l-pyrone (erythro, isomer 8, Example 13A(b)), d-pyrone (erythro, isomer 5, Example 13B(a)), l-pyrone (erythro, isomer 6, Example 13B(b)) for the corresponding d-pyrone (threo, isomer 3, Example l2-A(a)) and gave the corresponding pyran acetates the members of the group consisting of ll -acetoxy-3-( l ,2'dimethylheptyl)-6,6,9,trimethyl- 7,8,9,l0-tetrahydro-6H-dibenzo [b,d]pyran, threo, isomer 4, [01] ,(methanol, c 0.7); d-lacet0xy-3- 1,Z-dimethylheptyl)-6,6,9,trimethyl-7,8,9,10- tetrahydro-6H-dibenzo [b,d] pyran, threo, isomer 1, [a 1 +65 (methanol, c 06.); l-l-acetoxy-3(1,2-dimethylheptyl)-6,6,9-trimethyl-7,8,9,l0-tetrahydro-6H- dibenzo [b,d]pyran, threo, isomer 2, [11],, -l30 (methanol, c 0.8); dl -acetoxy-3-( l,2-dimethylheptyl)- 6,6,9-trimethyl-7,8,9, l0-tetrahydro-6H-dibenzo [b,d Jpyran, erythro, isomer 7, [oz],,+l05 (methanol, 0 0.7); ll-acetoxy-3-( l,2-dimethylheptyl)-6,6,9- methyl-7,8,9, l0-tetrahydro-6H-dibenzo[ b,d]pyran, erythro, isomer 8, [ah-93 (methanol, 0 0.5); d-lacetoxy-3-( 1,2-dimethylheptyl)-6,6,9-trimethyl 7,8,9,l0-tetrahydro-6H-dibenzo [b,d]pryan, erythro, isomer 5, [a] +94 (methanol, c 0.6); l-l-acetoxy-3- l,2-dimethylheptyl)-6,6,9-trimethyl-7,8,9,10- tetrahydro-6 H-dibenm[b,d]pyran, erythro, isomer 6, [01],, -l 10 (methanol, 0 0.6).

We claim:

CH CH Wherein When A is CH;, then Y is C H When A is C H then Y is -Cl-l and the compound being an optically active isomer.

dl -acetoxy3-( l ,2-dimethylheptyl 6,6,9 ,trimethyl-7,8 ,9, l 0-tetrahydro-6l-l-dibenzo [b,d] pyran, threo, [01],, 65.(methanol, c 0.6).

3. ll -acetoxy-3-( l ,2-dimethylheptyl)-6,6,9-

' trimethyl-7,8,9, l O-tetrahydro-6H-dibenzo [b,d]pyran,

threo, [ab 1 30 (methanol, c 0.8).

4. ll -acetoxy-3-( 1,2-dimethylheptyl )-6,6,9- trimethyl-7,8,9,l0-tetrahydro-6l-l-dibenzo [b,d] pyran, threo, [01],, 70 (mehtanol, c 0.7).

5. ll -acetoxy-3-( 1,2dimethylheptyl)-6,6,9- trimethyl-7 ,8,9, l O-tetrahydro-6H-dibenzo [b,d]pyran, erythro, [011 -1 10 (methanol, c 0.6).

6. The method for preparing isomers of l-acetoxy-3- (alkyl )-6,6,9-trimethyl-7,8 ,9, l0-tetrahydro-6l-ldibenzo [b,d]pyran comprising the steps of: (a) treating an isomeric mixture of an alkyl-dialkoxyhydrocinnamic acid with dicyclohexylamine forming the corresponding salt and filtrate I and hydrolyzing said salt in a solution comprising a loweralkyl alcohol and mineral acid to the erythro, dl-alkyl-dialkoxyhydrocinnamic acid, (b) treating said filtrate I with benzylamine forming the corresponding salt and hydrolyzing said salt in a solution comprising a loweralkyl alcohol and mineral acid to the threo dl-alkyl-dialkoxyhydrocinnamic acid (c) treating the compound selected from the group consisting of erythro and threo dl-alkyl-dialkoxyhydrocinnammethylbenzylamine producing the separate isomers of amine salts selected from the group consisting of derythro, l-erythro, d-threo and l-threo alkyl-dialkoxyhydrocinnamic'a-methylbenzylamine and hydrolyzing said separate amine salts in an aqueous alkaline solution, then acidifying to the four isomer acids selected from the group consisting of d -erythro, l-erythro, dthreo and l-threo alkyl-dialkoxyhydrocinnamic acid, (d) reducing said four isomer acids comprising lithium aluminum hydride and solvent with subsequent acidification to the alcohol isomers selected from the group consisting of d-erythro, l-erythro, l-threo and l-threo alkyl-(dialkoxyaryDalkanol, treating said alcohol isomers with P-toluenesulfonyl chloride to the esters, and reducing said esters with lithium aluminum hydride and solvent, to the octane isomers selected from the group consisting of d-erythro, l-erythro, d-threo and lthreo (dialkoxyaryl)alkyloctane, (e) treating said octane isomers with the separate optically-active form of 2-carbethoxy-5-methylcyclohexanone, solvent and phosphorus oxychloride and separating the eight isomers of l-hydroxy-3-(alkyl)-9-methyl-7,8,9,10- tetrahydro-6H-dibenzo[b,d]pyrone, (f) treating said eight pyrone isomers with methyl magnesium iodide producing isomers of 1-hydroxy-3-(alkyl)6,6,9- trimethyl-7,8,9, l 0-tetrahydro-6H-dibenzo[ b,d] pyran, (g) treating the isomers of the pyran with acetic anhydride converting the hydroxy group to an acetoxy group. 

2. d-1-acetoxy-3-(1,2-dimethylheptyl)-6,6,9,trimethyl-7,8,9,10-tetrahydro-6H -dibenzo (b,d)pyran, threo, ( Alpha )D + 65* (methanol, c 0.6).
 3. l-1-acetoxy-3-(1,2-dimethylheptyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H -dibenzo (b,d)pyran, threo, ( Alpha )D -130* (methanol, c 0.8).
 4. l-1-acetoxy-3-(1,2-dimethylheptyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H -dibenzo (b,d) pyran, threo, ( Alpha )D -70* , (mehtanol, c 0.7).
 5. l-1-acetoxy-3-(1,2-dimethylheptyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H -dibenzo (b,d)pyran, erythro, ( Alpha )D -110* (methanol, c 0.6).
 6. The method for preparing isomers of 1-acetoxy-3-(alkyl)-6,6, 9-trimethyl-7,8,9,10-tetrahydro-6H-dibenzo (b,d)pyran comprising the steps of: (a) treating an isomeric mixture of an alkyl-dialkoxyhydrocinnamic acid with dicyclohexylamine forming the corresponding salt and filtrate I and hydrolyzing said salt in a solution comprising a lower alkyl alcohol and mineral acid to the erythro, dl-alkyl-dialkoxyhydrocinnamic acid, (b) treating said filtrate I with benzylamine forming the corresponding salt and hydrolyzing said salt in a solution comprising a lower alkyl alcohol and mineral acid to the threo dl-alkyl-dialkoxyhydrocinnamic acid (c) treating the compound selected from the group consisting of erythro and threo dl-alkyl-dialkoxyhydrocinnamic acid with the separate optically-active form of Alpha -methylbenzylamine producing the separate isomers of amine salts selected from the group consisting of d-erythro, l-erythro, d-threo and l-threo alkyl-dialkoxyhydrocinnamic. Alpha -methylbenzylamine and hydrolyzing said separate amine salts in an aqueous alkaline solution, then acidifying to the four isomer acids selected from the group consisting of d-erythro, l-erythro, d-threo and l-threo alkyl-dialkoxyhydrocinnamic acid, (d) reducing said four isomer acids comprising lithium aluminum hydride and solvent with subsequent acidification to the alcohol isomers selected from the group consisting of d-erythro, l-erythro, l-threo and l-threo alkyl-(dialkoxyaryl)alkanol, treating said alcohol isomers with P-toluenesulfonyl chloride to the esters, and reducing said esters with lithium aluminum hydride and solvent, to the octane isomers selected from the group consisting of d-erythro, l-erythro, d-threo and l-threo (dialkoxyaryl)alkyloctane, (e) treating said octane isomers with the separate optically-active form of 2-carbethoxy-5-methylcyclohexanone, solvent and phosphorus oxychloride and separating the eight isomers of 1-hydroxy-3-(alkyl)-9-methyl-7,8, 9,10-tetrahydro-6H-dibenzo(b,d)pyrone, (f) treating said eight pyrone isomers with methyl magnesium iodide producing isomers of 1-hydroxy-3-(alkyl)-6,6,9-trimethyl-7,8,9,10-tetrahydro-6H-dibenzo( b,d)pyran, (g) treating the isomers of the pyran with acetic anhydride converting the hydroxy group to an acetoxy group. 